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Tumor-specific CD8 + T cells are exposed to persistent antigenic stimulation which induces a dysfunctional state called “exhaustion.” Though functioning to limit damage caused by immune response, T cell exhaustion leads to attenuated effector function whereby cytotoxic CD8 + T cells fail to control tumor progression in the late stage. This pathway is a dynamic process from activation to “progenitor exhaustion” through to “terminally exhaustion” with distinct properties. With the rapid development of immunotherapy via enhancing T cell function, new studies are dissecting the mechanisms and identifying specific biomarkers of dynamic differentiation during the process of exhaustion. Further, although immune checkpoint inhibitors (ICIs) have achieved great success in clinical practice, most patients still show limited efficacy to ICIs. The expansion and differentiation of progenitor exhausted T cells explained the success of ICIs while the depletion of the progenitor T cell pool and the transient effector function of terminally exhausted T cells accounted for the failure of immune monotherapy in the context of exorbitant tumor burden. Thus, combination strategies are urgent to be utilized based on the reduction of tumor burden or the expansion of the progenitor T cell pool. In this review, we aim to introduce the concept of homeostasis of the activated and exhausted status of CD8 + T cells in the tumor immune microenvironment, and present recent findings on dynamic differentiation process during T cell exhaustion and the implications for combination strategies in immune therapy.

Exosomes are representative extracellular vesicles (EV) derived from multivesicular endosomes (MVE) and have been described as new particles in the communication of neighborhood and/or distant cells by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and nucleotides including micro (mi) RNAs. Exosomes from immune cells and tumor cells act in part as a regulator in tumor immunology. CD8+ T cells that show potent cytotoxic activity against tumor cells reside as an inactive naïve form in the T‐cell zone of secondary lymphoid organs. Once receiving tumor‐specific antigenic stimulation by dendritic cells (DC), CD8+ T cells are activated and differentiated into effector CTL. Subsequently, CTL circulate systemically, infiltrate into tumor lesions through the stromal neovasculature where mesenchymal stromal cells, for example, mesenchymal stem cells (MSC) and cancer‐associated fibroblasts (CAF), abundantly exist, destroy mesenchymal tumor stroma in an exosome‐mediated way, go into tumor parenchyma, and attack tumor cells by specific interaction. DC‐derived and regulatory T (Treg) cell‐derived exosomes, respectively, promote and inhibit CTL generation in this setting. In this review, we describe the roles of exosomes from immune cells and tumor cells on the regulation of tumor progression. Tumor progression is regulated by immune cell‐released exosomes. CD8+ T‐cell exosomes prevent tumor invasion and metastasis by depletion of mesenchymal tumor stromal cells.

Current influenza A virus (IAV) vaccines stimulate antibody responses that are directed against variable regions of the virus, and are therefore ineffective against divergent strains. As CD8+ T cells target the highly conserved, internal IAV proteins, they have the potential to increase heterosubtypic immunity. Early T‐cell priming events influence lasting memory, which is required for long‐term protection. However, the early responding, IAV‐specific cells are difficult to monitor because of their low frequencies. Here, we tracked the dissemination of endogenous IAV‐specific CD8+ T cells during the initial phases of the immune response following IAV infection. We exposed a significant population of recently activated, CD25+CD43+ IAV‐specific T cells that were not detected by tetramer staining. By tracking this population, we found that initial T‐cell priming occurred in the mediastinal lymph nodes, which gave rise to the most expansive IAV‐specific CD8+ T‐cell population. Subsequently, IAV‐specific CD8+ T cells dispersed to the bronchoalveolar lavage and blood, followed by spleen and liver, and finally to the lung. These data provide important insight into the priming and tissue dispersion of an endogenous CD8+ T‐cell response. Importantly, the CD25+CD43+ phenotype identifies an inclusive population of early responding CD8+ T cells, which may provide insight into TCR repertoire selection and expansion. A better understanding of this response is critical for designing improved vaccines that target CD8+ T cells. We tracked the dissemination of endogenous IAV‐specific CD8+ T cells during the initial phases of the immune response following IAV infection. We exposed a significant population of recently activated CD25+CD43+ IAV‐specific T cells that were not detected by tetramer staining. Identification of this subset provides a method to investigate factors that impact early T‐cell priming, which is critical for understanding how to generate durable memory to infections and vaccines.

Immunosuppressive therapy prevents graft rejection but increases the risk of non-melanoma skin cancer (NMSC), especially in elderly kidney transplant recipients (KTR). In this study, we separately investigated the differentiation of CD8 regulatory T cells (Tregs) and responder T cells (Tresps) between healthy KTR without NMSC, KTR developing NMSC within two years after the enrolment, and KTR with NMSC at the time of enrolment. Antigen-unexperienced CCR7 CD45RA CD31 recent thymic emigrant (RTE) cells differentiate CD45RA CD31 memory (CD31 memory) cells, resting mature naïve (MN) cells or direct proliferation into CD45RA CD31 memory (CD31 memory) cells, consisting of both CCR7 CD45RA central memory (CM) and CCR7 CD45RA effector memory (EM) cells. We found that both RTE Treg and Tresp differentiation CD31 memory Tregs/Tresps was age-independently increased in KTR, who developed NMSC during the follow-up period, causing abundant CM Treg/Tresp production, which may be crucial for cancer immunity. These changes favored a strongly increased CD8 Treg/Tresp ratio, suggesting this ratio as a reliable marker for NMSC development in KTR. However, with age, this differentiation was replaced by increased conversion of resting MN Tregs/Tresps into CM Tregs/Tresps, which exhausted for Tresps but not for Tregs. In KTR with already existing NMSC at enrolment, differentiation was maintained conversion and proliferation of resting MN Tregs/Tresps, which however increasingly exhausted with age, especially for Tresps. This resulted in a strong accumulation of terminally differentiated effector memory (TEMRA) Tresps in elderly individuals. Patients with NMSC recurrence showed increased proliferation of resting MN Tregs/Tresps into EM Tregs/Tresps, which tended to exhaust more rapidly, particularly for Tresps, than in patients without NMSC recurrence. In conclusion, we provide evidence that immunosuppressive therapy inhibits differentiation of CD8 Tregs more than that of CD8 Tresps, resulting in an exhausted Tresp profile, thus providing a possible therapeutic approach to improve poor cancer immunity in elderly KTR.

Background Anti-PD-(L)1 immunotherapy has been recommended for non-small cell lung cancer (NSCLC) patients with lymph node metastases (LNM). However, the exact functional feature and spatial architecture of tumor-infiltrating CD8 + T cells remain unclear in these patients. Methods Tissue microarrays (TMAs) from 279 IA-IIIB NSCLC samples were stained by multiplex immunofluorescence (mIF) for 11 markers (CD8, CD103, PD-1, Tim3, GZMB, CD4, Foxp3, CD31, αSMA, Hif-1α, pan-CK). We evaluated the density of CD8 + T-cell functional subsets, the mean nearest neighbor distance (mNND) between CD8 + T cells and neighboring cells, and the cancer-cell proximity score (CCPS) in invasive margin (IM) as well as tumor center (TC) to investigate their relationships with LNM and prognosis. Results The densities of CD8 + T-cell functional subsets, including predysfunctional CD8 + T cells (T predys ) and dysfunctional CD8 + T cells (T dys ), in IM predominated over those in TC ( P  < 0.001). Multivariate analysis identified that the densities of CD8 + T predys cells in TC and CD8 + T dys cells in IM were significantly associated with LNM [OR = 0.51, 95%CI (0.29–0.88), P  = 0.015; OR = 5.80, 95%CI (3.19–10.54), P  < 0.001; respectively] and recurrence-free survival (RFS) [HR = 0.55, 95%CI (0.34–0.89), P  = 0.014; HR = 2.49, 95%CI (1.60–4.13), P  = 0.012; respectively], independent of clinicopathological factors. Additionally, shorter mNND between CD8 + T cells and their neighboring immunoregulatory cells indicated a stronger interplay network in the microenvironment of NSCLC patients with LNM and was associated with worse prognosis. Furthermore, analysis of CCPS suggested that cancer microvessels (CMVs) and cancer-associated fibroblasts (CAFs) selectively hindered CD8 + T cells from contacting with cancer cells, and were associated with the dysfunction of CD8 + T cells. Conclusion Tumor-infiltrating CD8 + T cells were in a more dysfunctional status and in a more immunosuppressive microenvironment in patients with LNM compared with those without LNM.

Under conditions of chronic antigen stimulation, such as persistent viral infection and cancer, CD8 T cells may diminish effector function, which has been termed \"exhaustion.\" Expression of inhibitory Receptors (iRs) is often regarded as a hallmark of \"exhaustion.\" Here we studied the expression of eight different iRs by CD8 T cells of healthy humans, including CTLA-4, PD1, TIM3, LAG3, 2B4, BTLA, CD160, and KLRG1. We show that many iRs are expressed upon activation, and with progressive differentiation to effector cells, even in absence of long-term (\"chronic\") antigenic stimulation. In particular, we evaluated the direct relationship between iR expression and functionality in CD8 T cells by using anti-CD3 and anti-CD28 stimulation to stimulate all cells and differentiation subsets. We observed a striking up-regulation of certain iRs following the cytokine production wave, in agreement with the notion that iRs function as a negative feedback mechanism. Intriguingly, we found no major impairment of cytokine production in cells positive for a broad array of iRs, as previously shown for PD1 in healthy donors. Rather, the expression of the various iRs strongly correlated with T cell differentiation or activation states, or both. Furthermore, we analyzed CD8 T cells from lymph nodes (LNs) of melanoma patients. Interestingly, we found altered iR expression and lower cytokine production by T cells from metastatic LNs, but also from non-metastatic LNs, likely due to mechanisms which are not related to exhaustion. Together, our data shows that expression of iRs per se does not mark dysfunctional cells, but is rather tightly linked to activation and differentiation. This study highlights the importance of considering the status of activation and differentiation for the study and the clinical monitoring of CD8 T cells.

Background Relationship between cancer cell glycolysis and the landscape of tumor immune microenvironment in human cancers was investigated. Methods Forty-one fresh lung adenocarcinoma (ADC) tissues were analyzed using flow cytometry for comprehensive immunoprofiling. Formalin-fixed tissues were immunostained for hexokinase-2 (HK2) to assess cancer cell glycolysis. For validation, formalin-fixed tissues from 375 lung ADC, 118 lung squamous cell carcinoma (SqCC), 338 colon ADC, and 78 lung cancer patients treated with anti-PD-1/PD-L1 immunotherapy were immunostained for HK2, CD8, and FOXP3. Results Based on immunoprofiling of lung ADC, HK2 tumor expression was associated with the composition of lymphoid cells rather than myeloid cells. High HK2 tumor expression was associated with immunosuppressive/pro-tumorigenic features, especially decreased ratio of CD8 + T-cells to Tregs (rho = −0.415, P  = 0.012). This correlation was also confirmed in four different cohorts including lung ADC and SqCC, colon ADC, and the immunotherapy cohort (rho = −0.175~-0.335, all P  < 0.05). A low CD8 + T-cell to Treg ratio was associated with poor progression-free survival and overall survival in lung SqCC patients, and a shorter overall survival in the immunotherapy cohort (all, P  < 0.05). Conclusion An increase in HK2 expression may contribute to shaping the immunosuppressive/pro-tumorigenic tumor microenvironment by modulating the CD8 + T-cell to Treg ratio. Targeting tumor HK2 expression might be a potential strategy for enhancing anti-tumor immunity.

Older adults often show signs of impaired CD8+ T‐cell immunity, reflected by weaker responses against new infections and vaccinations, and decreased protection against reinfection. This immune impairment is in part thought to be the consequence of a decrease in both T‐cell numbers and repertoire diversity. If this is indeed the case, a strategy to prevent infectious diseases in older adults could be the induction of protective memory responses through vaccination at a younger age. However, this requires that the induced immune responses are maintained until old age. It is therefore important to obtain insights into the long‐term maintenance of the antigen‐specific T‐cell repertoire. Here, we review the literature on the maintenance of antigen‐experienced CD8+ T‐cell repertoires against acute and chronic infections. We describe the complex interactions that play a role in shaping the memory T‐cell repertoire, and the effects of age, infection history, and T‐cell avidity. We discuss the implications of these findings for the development of new vaccination strategies to protect older adults. In this review, we aim to provide insight in the maintenance of antigen‐experienced CD8+ T‐cell clones during life. We describe what is already known on the effect of age on the virus‐specific T‐cell repertoire and discuss the contribution of infection history in shaping the repertoire. Insight in factors shaping the T‐cell repertoire will help to improve the protective memory response against infectious diseases in older adults.

Background In recent years, immunotherapy has made significant progress. However, the understanding of the heterogeneity and function of T cells, particularly CD8 + T cells, in cervical cancer (CESC) microenvironment remains insufficient. We aim to characterize the heterogeneity, developmental trajectory, regulatory network, and intercellular communication of CD8 + T cells in cervical squamous cell carcinoma and to construct a prognostic risk model based on the transcriptomic characteristics of CD8 + T cells. Methods We integrated single-cell RNA sequencing data from CESC tumor samples with bulk transcriptome data from TCGA and GEO databases. We identified CD8 + T cell subsets in the CESC microenvironment, revealing significant interactions between CD8 + T cells and other cell types through intercellular communication analysis. Pseudotime trajectory analysis revealed dynamic transcriptional regulation during CD8 + T cell differentiation and functional acquisition processes. We constructed a transcriptional regulatory network for CESC CD8 + T cells, identifying key transcription factors. Based on CD8 + T cell-related genes, a prognostic risk model comprising eight core genes was developed and validated using machine learning. Results We identified four distinct CD8 + T cell subsets, namely progenitor, intermediate, proliferative, and terminally differentiated, each exhibiting unique transcriptomic characteristics and functional properties. CD8 + T cell subsets interact with macrophages through different ligand-receptor networks, including the CCL-CCR signaling pathway and costimulatory molecules. Sorafenib was identified as a potential immunotherapeutic drug through drug screening. Experimental validation demonstrated that sorafenib enhances the cytotoxicity of CD8 + T cells by increasing the secretion of IFN-γ and TNF-α, thereby significantly inhibiting the invasiveness and survival of CESC cells. Conclusions Our study provides valuable insights into the heterogeneity and functional diversity of CD8 + T cells in CESC. We demonstrate that a CD8 + T cell-related prognostic signature may serve as a potential tool for risk stratification in patients with CESC. Additionally, our finding suggests that sorafenib could be a promising therapeutic candidate for improving antitumor immunity in this patient population.

Background Immunosuppression is a significant factor contributing to the poor prognosis of cancer. S100P , a member of the S100 protein family, has been implicated in various cancers. However, its role in the tumor microenvironment (TME) of pancreatic cancer remains unclear. This study aimed to investigate the potential impact of S100P on TME characteristics in patients with pancreatic cancer. Methods Multiple data (including microarray, RNA-Seq, and scRNA-Seq) were obtained from public databases. The expression pattern of S100P was comprehensively evaluated in RNA-Seq data and validated in four different microarray datasets. Prognostic value was assessed through Kaplan-Meier plotter and Cox regression analyses. Immune infiltration levels were determined using the ESTIMATE and ssGSEA algorithms and validated at the single-cell level. Spearman correlation test was used to examine the correlation between S100P expression and immune checkpoint genes, and tumor mutation burden (TMB). DNA methylation analysis was performed to investigate the change in mRNA expression. Reverse transcription PCR (RT-PCR) and immunohistochemical (IHC) were utilized to validate the expression using five cell lines and 60 pancreatic cancer tissues. Results This study found that S100P was differentially expressed in pancreatic cancer and was associated with poor prognosis ( P  < 0.05). Notably, S100P exhibited a significant negative-correlation with immune cell infiltration, particularly CD8 + T cells. Furthermore, a close association between S100P and immunotherapy was observed, as it strongly correlated with TMB and the expression levels of TIGIT , HAVCR2 , CTLA4 , and BTLA ( P  < 0.05). Intriguingly, higher S100P expression demonstrated a negative correlation with methylation levels (cg14323984, cg27027375, cg14900031, cg14140379, cg25083732, cg07210669, cg26233331, and cg22266967), which were associated with CD8 + T cells. In vitro RT-PCR validated upregulated S100P expression across all five pancreatic cancer cell lines, and IHC confirmed high S100P levels in pancreatic cancer tissues ( P  < 0.05). Conclusion These findings suggest that S100P could serve as a promising biomarker for immunosuppressive microenvironment, which may provide a novel therapeutic way for pancreatic cancer.